BIDIRECTIONAL INTERACTION OF VALPROATE AND LAMOTRIGINE IN HEALTHY-SUBJECTS

Objective: To evaluate the steady-state pharmacokinetics of lamotrigin e and valproate at three dosing levels of lamotrigine in normal volunt eers receiving steady-state therapeutic doses of valproate, Methods: T his was an open-label, randomized, three-way crossover study of 18 nor mal mate volunteers, Subjects received oral valproate (500 mg Depakote twice a day) throughout the study, Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) fo r 1 week each, with a 2-week washout period between lamotrigine treatm ent periods, Valproate and lamotrigine trough plasma samples were dete rmined by a capillary gas chromatography method and immunofluorometric assay, respectively, Urine samples were assayed for 11 valproate meta bolites by gas chromatography/mass spectrometry, Results: When compare d to other studies in which lamotrigine was administered with no concu rrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug, The additi on of lamotrigine was associated with a small but significant 25% decr ease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pent enoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E), 4-diene-valproate], was unaffected by lamotrigine administration, Conc lusions: As a consequence of the interaction between lamotrigine and s odium valproate, a dosage reduction of lamotrigine should be considere d in patients taking a combination of valproate and lamotrigine.